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Finbarr Foy,1 Giuseppe Luna,1 Jorge Martinez,1 Zach Nizich,2 Jason Seet,2 Katie Lie,2 Bruce Sunderland,1 Petra Czarniak11School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia; 2Sir Charles Gairdner Hospital, Department of Pharmacy, Nedlands, WA, AustraliaPurpose: To evaluate the stability of meropenem trihydrate in elastomeric infusion devices at a range of selected concentrations (6, 12, 20 and 25 mg/mL) at ambient, refrigeration and freezing temperatures.Methods: Meropenem Ranbaxy® (meropenem trihydrate equivalent to anhydrous meropenem 1 g) vials for injection were reconstituted with 0.9% sodium chloride and adjusted to pH 6.5 using 1 M hydrochloric acid. Following preparation, solutions were stored for 7 days at either 6.7°C in elastomeric infusion devices or at −19°C in glass vials; samples of each concentration were removed from the infusion devices at specific time-points and stored for 24 hrs at 22.5°C. All solutions were assayed at specific time-points using high-performance liquid chromatography. Forced degradation in hydrochloric acid, sodium hydroxide and hydrogen peroxide was carried out at 40°C.Results: The lowest concentration of meropenem (6 mg/mL) displayed the highest stability. It maintained >90% of its initial concentration for up to 144 hrs when stored at 6.7°C and 72 hrs following 24 hrs storage at 22.5°C, having been initially refrigerated for 48 hrs. Meropenem 20 mg/mL required immediate administration following preparation under ambient temperatures, whilst meropenem 25 mg/mL did not remain stable following 24 hrs storage at ambient temperatures. Frozen meropenem solutions displayed good stability in all concentrations but were physically unstable due to the formation of a precipitate.Conclusion: At lower concentrations, meropenem showed suitable stability for storage and administration in elastomeric infusion devices, at refrigerated temperatures. To enhance the stability of lower concentration solutions when exposed to ambient temperatures by ambulatory patients, a more adept method of maintaining lower temperatures that reflect refrigerated conditions for elastomeric infusion devices should be devised.Keywords: meropenem, stability, HPLC, elastomeric infusion device, OPAT

IκBα resides in the cytosol where it retains the inducible transcription factor NF-κB. We show that IκBα also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF-κB that accumulate high amounts of mitochondrial IκBα as a NF-κB target gene. 3T3 IκBα(-/-) cells also become protected from apoptosis when IκBα is specifically reconstituted at the OMM. Using various IκBα mutants, we demonstrate that apoptosis inhibition and NF-κB inhibition can be functionally and structurally separated. At mitochondria, IκBα stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When IκBα is reduced in tumour cells with constitutively active NF-κB, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of IκBα in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF-κB., (© 2014 The Authors.)

The permeability transition pore (PT-pore) mediates cell death through the dissipation of the mitochondrial membrane potential (ΔΨm). Because the exact composition of the PT-pore is controversial, it is crucial to investigate the actual molecular constituents and regulators of this complex. We found that mitochondrial creatine kinase-1 (CKMT1) is a universal and functionally necessary gatekeeper of the PT-pore, as its depletion induces mitochondrial depolarization and apoptotic cell death. This can be inhibited efficiently by bongkrekic acid, a compound that is widely used to inhibit the PT-pore. However, when the 'classical' PT-pore subunits cyclophilin D and VDAC1 are pharmacologically inhibited or their expression levels reduced, mitochondrial depolarization by CKMT1 depletion remains unaffected. At later stages of drug-induced apoptosis, CKMT1 levels are reduced, suggesting that CKMT1 downregulation acts to reinforce the commitment of cells to apoptosis. A novel high-molecular-mass CKMT1 complex that is distinct from the known CKMT1 octamer disintegrates upon treatment with cytotoxic drugs, concomitant with mitochondrial depolarization. Our study provides evidence that CKMT1 is a key regulator of the PT-pore through a complex that is distinct from the classical PT-pore.

Background: To improve pain management, the Veterans Health Administration launched the "Pain as the 5th Vital Sign" initiative in 1999, requiring a pain intensity rating (0 to 10) at all clinical encounters., Objective: To measure the initiative's impact on the quality of pain management., Design: We retrospectively reviewed medical records at a single medical center to compare providers' pain management before and after implementing the initiative and performed a subgroup analysis of patients reporting substantial pain (> or =4) during a postimplementation visit., Participants: Unique patient visits selected from all 15 primary care providers of a general medicine outpatient clinic., Measurements: We used 7 process indicators of quality pain management, based on appropriately evaluating and treating pain, to assess 300 randomly selected visits before and 300 visits after implementing the pain initiative., Results: The quality of pain care was unchanged between visits before and after the pain initiative (P>.05 for all comparisons): subjective provider assessment (49.3% before, 48.7% after), pain exam (26.3%, 26.0%), orders to assess pain (11.7%, 8.3%), new analgesic (8.7%, 11.0%), change in existing analgesics (6.7%, 4.3%), other pain treatment (11.7%, 13.7%), or follow-up plans (10.0%, 8.7%). Patients (n=79) who reported substantial pain often did not receive recommended care: 22% had no attention to pain documented in the medical record, 27% had no further assessment documented, and 52% received no new therapy for pain at that visit., Conclusions: Routinely measuring pain by the 5th vital sign did not increase the quality of pain management. Patients with substantial pain documented by the 5th vital sign often had inadequate pain management.

Purpose: To understand which specific student behaviors predict performance ratings from standardized patients and behavioral scientist preceptors., Method: In 1996-98, objective, real-time ratings of student verbal and nonverbal behaviors were conducted on 75 videotaped interviews between second-year medical students and standardized patients at University of North Carolina at Chapel Hill School of Medicine. The coding system used in these analyses was developed based on evidence-based literature reviews and used software that provides for real-time recording; 30 nonverbal and 33 behaviors were coded. The coded behaviors were then compared with four ratings: a global rating of the encounter by the standardized patient, a summary score derived from a checklist completed by the standardized patient, a global rating of the encounter by a behavioral science preceptor who observed the encounter, and a summary score derived from a checklist completed by the preceptor., Results: Analyses identified strong correlations between all four of the preceptor and patient ratings, a strong independent effect of case scenario, and significant between-rater variation. When multivariable analysis was used to predict these global ratings based on coding of specific behaviors, a relatively high proportion of observer variation was explained by a small group of coded behaviors., Conclusions: This study suggests that the coding of specific behaviors may hold promise as a student evaluation technique thereby improving medical training techniques and ultimately enhancing the communication skills in physician-patient encounters. It also illustrates the need to better clarify which specific behaviors are most critical in influencing patient satisfaction.

We report the photometric observation of a polychromatic laser guide star (PLGS) using the AVLIS laser at the Lawrence Livermore National Laboratory (LLNL). The process aims at providing a measurement of the tilt of the incoming wave front at a telescope induced by atmospheric turbulence. It relies on the two-photon coherent excitation of the 4D5/2 energy level of sodium atoms in the mesosphere. We used two laser beams at 589 and 569 nm, with a maximum total average output power of approximately 350 W. For the purpose of photometric calibration, a natural star was observed simultaneously through the same instrument as the PLGS at the focus of the LLNL 50-cm telescope. Photometric measurements of the 330-nm return flux confirm our previous theoretical studies that the PLGS process should allow us at a later stage to correct for the tilt at wavelengths as short as approximately 1 microm at good astronomical sites. They show also that, at saturation of two-photon coherent absorption in the mesosphere, the backscattered flux increases by a factor of approximately 2 when the pulse repetition rate decreases by a factor of 3 at constant average power. This unexpected behavior is briefly discussed.